USOO8828440B2 (12) United States Patent (10) Patent No.: US 8,828,440 B2 Bodick et al. (45) Date of Patent: Sep. 9, 2014 (54) CORTICOSTEROIDS FOR THE TREATMENT OTHER PUBLICATIONS OF JOINT PAIN Anderson et al. “Biodegradation and Biocompatibility of PLA and (75) Inventors: Neil Bodick, Boston, MA (US); Robert PLGA Microspheres.” Adv. Drug Deliv Rev. 28(1997):5-24. C. Blanks, Auburndale, MA (US); Ayral et al. “Synovitis: A Potential Predictive Factor of Structural Anjali Kumar, Belmont, MA (US); Progression of Medial Tibiofemoral Knee Osteoarthritis—Results of Michael D. Clayman, Gloucester, MA a 1 Year Longitudinal Arthroscopic Study in 422 Patients.” (US); Mark Moran, Orinda, CA (US) OsteoArth. Cartilage. 13(2005):361-367. Bouissou et al. “Poly(lactic-co-glycolic acid) Microspheres.” Poly (73) Assignee: Flexion Therapeutics, Inc., Burlington, mers in Drug Delivery. Chapter 7(2006): 81-99. Cleek et al. “Microparticles of Poly(DL-lactic-co-glycolic acid)/ MA (US) poly(ethylene glycol) Blends for Controlled Drug Delivery.” J. Con (*) Notice: Subject to any disclaimer, the term of this trol. Relase. 48(1997): 259-268. Coopman et al. “Identification of Cross-Reaction Patterns in Allergic patent is extended or adjusted under 35 Contact Dermatitis from Topical Corticosteroids.” Br: J. Dermatol. U.S.C. 154(b) by 0 days. 121 (1989):27-34. Derendorfetal. “Clinical PKPDModelling as a Tool in Drug Devel (21) Appl. No.: 13/422,994 opment of Corticosteroids.” Int. J. Clin. Pharmacol. Ther. 35.10(1997):481-488. (22) Filed: Mar 16, 2012 Derendorf et al. “Pharmacokinetics and Pharmacodynamics of Glucocorticoid Suspensions After Intra-Articular Administration.” (65) Prior Publication Data Clin. Pharmacol. Ther: 39.3(1986):313-317. US 2012/O288534 A1 Nov. 15, 2012 Eckstein et al. “Magnetic Resonance Imaging (MRI) of Articular Cartilage in Knee Osteoarthritis (OA): Morphological Assessment.” OsteoArth. Cartilage. 14(2006):A46-A75. Related U.S. Application Data Foti et al. "Contact Allergy to Topical Corticosteroids: Update and (63) Continuation of application No. 13/198,168, filed on Review on Cross-Sensitization.” Recent Pat. Inflamm. Allergy Drug Aug. 4, 2011, now abandoned. Discov. 3.1(2009):33-39. Habib. "Systemic Effects of Intra-Articular Corticosteroids.” Clin. (60) Provisional application No. 61/370,666, filed on Aug. Rheumatol. 28.7(2009):749-756. 4, 2010. Hepper et al. “The Efficacy and Duration of Intra-Articular Corticosteroid Injection for Knee Osteoarthritis: A Systematic (51) Int. Cl. Review of Level I Studies.” J. Am. Acad. Orthop. Surg. A6 IK 9/14 (2006.01) 17.10(2009):638-646. A 6LX 9/50 (2006.01) Hill et al. “Synovitis Detected on Magnetic Resonance Imaging and A6 IK3I/56 (2006.01) its Relation to Pain and Cartilage Loss in Knee Osteoarthritis.” Ann. A 6LX3/573 (2006.01) Rheum. Dis. 66(2007): 1599-1603. A6 IK9/00 (2006.01) Houetal. “In Situ Gelling Hydrogels Incorporating Microparticles as A6 IK 9/16 (2006.01) Drug Delivery Carriers for Regenerative Medicine.” J. Pharm. Sci. (52) U.S. Cl. 97.9(2008):3972-3980. CPC ............. A61 K9/1647 (2013.01); A61 K3I/573 Kirwan et al. “Effects of Glucocorticoids on Radiological Progres (2013.01); A61 K9/0024 (2013.01); A61 K sion in Rheumatoid Arthritis.” Cochrane Database Syst. Rev. (2009). 9/0019 (2013.01); A61 K9/1641 (2013.01); (Continued) A61 K9/1694 (2013.01) USPC ............................ 424/489: 424/497: 514/181 (58) Field of Classification Search Primary Examiner — David J Blanchard None Assistant Examiner — Tigabu Kassa See application file for complete search history. (74) Attorney, Agent, or Firm — Cooley LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Corticosteroid microparticle formulations are provided for 4.293,539 A 10/1981 Ludwig et al. use for treating pain, including pain caused by inflammatory 7,261,529 B2 8/2007 Persyn et al. 7,758,778 B2 7/2010 Persyn et al. diseases such as osteoarthritis or rheumatoid arthritis, and for 2004/O105821 A1* 6/2004 Bernstein et al. ............... 424/46 slowing, arresting or reversing structural damage to tissues 2005/OO31549 A1 2/2005 Quay et al. caused by an inflammatory disease, for example damage to 2007/0053990 A1 3/2007 Persyn et al. articular and/or peri-articular tissues caused by osteoarthritis 2007,0264.343 A1 11/2007 Bernstein et al. or rheumatoid arthritis. Corticosteroid microparticle formu 2008/0248122 A1 10/2008 Rashba-Step et al. 2008/0317805 A1 12/2008 McKay et al. lations are administered locally as a Sustained release dosage 2009, OO35253 A1 2/2009 Wright et al. form (with or without an immediate release component) that 2009, O123546 A1 5, 2009 Ashton et al. results in efficacy accompanied by clinically insignificant or no measurable effect on endogenous cortisol production. FOREIGN PATENT DOCUMENTS WO WO-95.13799 A1 5, 1995 10 Claims, 30 Drawing Sheets US 8,828.440 B2 Page 2 (56) References Cited Morlocket al. “Erythropoietin Loaded Microspheres Prepared from Biodegradable LPLG-PEO-LPLG Triblock Copolymers: Protein OTHER PUBLICATIONS Stabilization and in-vitro Release Properties.” J. Control. Release. 56.1-3(1998): 105-115. La Rochelle et al. “Recovery of the Hypothalamic-Pituitary-Adrenal Rojas et al. “Microdialysis of Triamcinolone Acetonide in Rat Muscle.” J. Pharm. Sci. 92.2(2003):394-397. (HPA) Axis in Patients with Rheumatic Diseases Receiving Low van den Berg et al. “Synovial Mediators of Cartilage Damage and Dose Prednisone.” Am. J. Med. 95(1993):258-264. Repair in Osteoarthritis.” Osteoarthritis. Brandt et al., eds. Oxford: Lo et al. "Bone Marrow Lesions in the Knee are Associated with Oxford University Press. 7.2.3 (2003): 147-155. Increased Local Bone Density.” Arth. Rheum. 52.9(2005):2814 Yeh. “The Stability of Insulin in Biodegradable Microparticles Based 2821. on Blends of Lactide Polymers and Polyethylene Glycol.” J. Lo et al. “The Ratio of Medial to Lateral Tibial Plateau Bone Mineral Microencapsul. 17.6(2000):743-756. Density and Compartment-Specific Tibiofemoral Osteoarthritis.” Zentner et al. "Biodegradable Block Copolymers for Delivery of OsteoArth. Cartilage. 14(2006):984-990. Proteins and Water-Insoluble Drugs.” J. Control. Release. Meibohm et al. “Mechanism-Based PK/PD Model for the 72(2001):203-215. Lymphocytopenia Induced by Endogenous and Exogenous Corticosteroids.” Int. J. Clin. Pharmacol. Ther: 37.8(1999):367-376. * cited by examiner U.S. Patent Sep. 9, 2014 Sheet 1 of 30 US 8,828,440 B2 FIG. 1 tra-articular COf Cetration - - - - - - - - - - - - - - - - - - - - - - intra-articular concentration required for efficacy Concentration in plasma associated with PA axis suppression L. H. - - - - - - - - - - - - - - - - - e Concentration in piasma ise post in tra articiar injection of sistaired release corticosteroid FIG. 2 TCA40mg EC50 (ng/mL) U.S. Patent Sep. 9, 2014 Sheet 2 of 30 US 8,828,440 B2 FIG. 3 -BPA 7mg EC50 (ng/mL) ---TCA 40 mg EC50 (ng/mL) -THCA 20 mg EC50 (ng/mL) 1 5 1.O O 50 1OO 150 2OO 250 300 350 4OO Time (h) U.S. Patent Sep. 9, 2014 Sheet 3 of 30 US 8,828,440 B2 0'09 88segg. A &:3SEgg, U.S. Patent Sep. 9, 2014 Sheet 4 of 30 US 8,828,440 B2 U.S. Patent Sep. 9, 2014 Sheet 5 Of 30 US 8,828,440 B2 O?000||O O| ----^ O\-|0.08 |0.07 |0.02 8:35 egg: A U.S. Patent Sep. 9, 2014 Sheet 6 of 30 US 8,828,440 B2 FIG. 5 100 . ; 90 m. 3. 80 70 --------------------------------0----------------------------------- 60 o S$ 50 $ 40 -/-.-0-25%. TCAPLGA75:25 30 20 s 10 O O 10 2O 3O Days FIG. 6 25%. TCAPLGA 75:25 -0-Adjusted Dose (mg/day) - - - 5% COrtisol Inhibition - - - -35% COrtisol Inhibition DOSe - - - - - - - - - - - - 40% COrtisol Inhibition DOSe H - H - H - H - H - - - - a 50% COrtisol Inhibition DOSe 10 15 2O 25 3O U.S. Patent Sep. 9, 2014 Sheet 7 Of 30 US 8,828,440 B2 FIG. 7 25%. TCAPLGA 75:25 -0- Adjusted Dose (mg/day) - - - 5% COrtisOl Inhibition - - - - 35% COrtisol Inhibition DOSe 40% COrtisol Inhibition DOSe 50% COrtisO Inhibition DOSe FIG. 8 100 90 8O 70 1 5060 1 40 / -0-25%. TCAPLGA 75:25 30 10 7 10 20 3O DayS U.S. Patent Sep. 9, 2014 Sheet 8 of 30 US 8,828,440 B2 FIG. 9 25% TCAPLGA 75:25 8.O 7.O -0-Adjusted DOSe (mg/day) 6.O - - -5% COrtisol 5.O Inhibition 4.0 - - - -35% COrtisol 3.O Inhibition DOSe 2.0 40% COrtisol Inhibition DOSe 1.O 50% COrtisOl O.O Inhibition DOSe -10 0 FIG. 10 25%. TCAPLGA 75:25 -0-Adjusted Dose (mg/day) - - - 5% COrtisol Inhibition - - - -35% COrtisol Inhibition DOSe 40% COrtisol Inhibition DOSe 50% COrtisol Inhibition DOSe U.S. Patent Sep. 9, 2014 Sheet 9 Of 30 US 8,828,440 B2 FIG 11 25%. TCA 5% PEG 1450/PLGA 75:25 1 OO 90 8O 70 60 - 25% TCA 5% PEG 50 145O/PLGA75:25 40 30 20 10 z 20 Days FIG. 12 25%. TCA 10% PEG 335OIPLGA 75:25 1 OO 90 8O 70 - 25%TCA 10%PEG 60 335O/PLGA75:25 50 40 30 2O 10 - 3O Days U.S. Patent Sep. 9, 2014 Sheet 10 of 30 US 8,828,440 B2 FIG. 13 25%. TCA 5% PEG 1450/PLGA 75:25 -0- Adjusted Dose (mg/day) - - - 5% COrtisol Inhibition - - - -35% COrtisol Inhibition DOSe 40% COrtisol Inhibition DOSe 50% COrtisol O 10 2O 30 Inhibition DOSe -1.0 - FIG. 14 25% TCA 10% PEG 3350/PLGA 75:25 7.O 6.O M -0- Adjusted(mg/day) Dose 5.0 | \ - - - 5% COrtisO 4.O Inhibition 3.0 ...Y - - - -35% COrtisol -S Inhibition DOSe 2.01.0 seaseO 40%Inhibition COrtisol DOSe 0.0-R F FEF RF FEF - F.